ORPHAN DRUGS: AN EMERGING ERA IN CLINICAL RESEARCH
04 Dec 2018
Orphan drug is a drug or biologic that intends to treat a rare disease or condition affecting fewer than 200,000 persons in the United States or a drug or biologic which will not be profitable within 7 years following approval by the U.S. Food & Drug Administration as per the 1984 amendment of the U.S. Orphan Drug Act. Orphan diseases are those diseases which occur in less than 200,000 persons in the United States. As per World Health Organization, a disease with a prevalence of 1 or less, per 1000 population is defined as a rare disease or an orphan disease. Reviews suggest that there are about 6000 to 8000 rare diseases in the world which affect 5-7 % (~ 400 million in the world) of the population in different countries.
Few orphan diseases:
-Hutchinson Gilford Progeria which affects just one in 8 million people and it results in rapid appearance of aging
-Fields’ disease, which is believed to only affect twins, and it results in muscular deterioration
-Brugada syndrome which affects just five in 10,000 people, and it causes heart arrythmias
Approved orphan drugs by 2017 in Europe:
-Mannitol (for treatment of cystic fibrosis)
-Para aminosalicylic acid (indicated for use as part of an appropriate combination regimen for multi-drug resistant tuberculosis)
-Tasimelteon (for treatment of non-24-hour sleep-wake disorder)
-Riociguat (for the treatment of chronic thromboembolic pulmonary hypertension)
Orphan Drug Act (ODA)
The Orphan Drug Act was signed in 1983 to facilitate the development of drugs for rare diseases and to motivate the sponsors to drive the research towards the evolution of drugs or molecules for the treatment of rare diseases or conditions. Several economic incentives were created through ODA to stimulate orphan drug development and marketing, such as:
-50% of tax credits for clinical research and testing expenses
-7 years marketing exclusivity period post-approval that begins on the date of FDA approval for the designated orphan indication. During the exclusivity period, the FDA cannot approve a NDA (New Drug Application) or a generic drug application for the same product and for the same rare disease indication.
Exclusive approval protects only the approved indication or use of a drug. FDA may later approve the drug for additional indication or uses within the rare disease not protected by the exclusive approval. If the sponsor who obtains approval for these new indications has orphan-drug designation, FDA will consider a new orphan-drug exclusive approval for these new indications from the date of approval of the drug for such new indications.
Orphan Drug Designation Application (ODDA)
A sponsor may file an application for the orphan drug designation at any time prior to submission of a marketing application for orphan indication according to orphan drug amendment of 1988.
A sponsor must have a detailed description of the drug to file for an orphan drug designation, such as:
- Generic and trade name of the drug (if any) or the chemical name or a meaningful descriptive name of the drug
- Active moiety of the drug if it is composed of small molecules or principal molecular structural features if it is composed of macromolecules
- Its physical and chemical properties
-Description of the rare disease for which the drug has been investigated, the proposed use of the drug and the reasons why such therapy is needed.
All relevant data from in vitro laboratory studies, preclinical efficacy studies (in animal model) and clinical experience with the drug in the rare disease whether positive, negative, or inconclusive.
-A description of the drug
Orphan-drug designation application can be submitted for a previously unapproved drug, or for a new use for an already marketed drug. More than one sponsor may receive orphan-drug designation of the same drug for the same rare disease or condition.
Sponsor may request for an orphan drug designation for the drug which affects only a subset of population with a particular disease (Orphan subset).
Office of Orphan Products Development (OOPD)
The FDA Office of Orphan Products Development (OOPD) determines if a drug qualifies as an orphan product for which they evaluate scientific and clinical data submissions from sponsors to identify and designate products for rare diseases. OOPD furnishes incentives to stimulate development of products for rare diseases, and they have successfully approved marketing of 600 drugs and biologic products for rare diseases since 1983 up to August 2017.
Clinical Research for Orphan drugs
Globally, clinical trials on rare diseases are ongoing with the approach of difficult to find and difficult to treat patients. Recruitment of patients and sites, engagement of regulatory and stakeholders and strategic planning is key for successful rare disease clinical research which would result in increased FDA approval rate for rare diseases.
Research is ongoing for X-linked Adrenoleukodystrophy disease with the drug MIN-102 completing a Phase-I trial. X-linked Adrenoleukodystrophy mainly affects the nervous system and adrenal glands and MIN-102 is Peroxisome proliferator-activated receptor-gamma agonist.
Other clinical trials ongoing for rare diseases are:
-Chronic vasculitis which causes inflammation of blood vessels in vital organs such as kidney, lung and brain
-Osteogenesis Imperfecta which cause bones to break easily
-Deficiency of pyruvate dehydrogenase complex (PDC)
-Disorder of Urea cycle which is caused by the liver’s inability to breakdown ammonia from protein; ammonia then accumulates resulting in toxicity to the brain